Air pollution, Alzheimer's Disease and Related Outcomes

项目摘要/摘要 阿尔茨海默病和相关痴呆症的负担很大，而且还在不断增加。我们没有疾病- 修改大多数痴呆症亚型的治疗方法，包括阿尔茨海默病痴呆症和最近 阿尔茨海默病的治疗试验一直令人失望。因此，找出预防或拖延的方法 阿尔茨海默氏症和相关的痴呆症可能是我们减轻疾病负担的最佳选择。环境空气 污染暴露是预防或延缓阿尔茨海默病及相关疾病的干预措施的一个有希望的目标 痴呆症。虽然现有证据表明环境空气污染暴露与认知健康和痴呆症有关 具有提示性，但不足以证明采取行动是正当的。为了建议或制定有效的干预措施 通过减少环境空气污染暴露来减轻痴呆症负担，我们必须首先确定 特定的污染物影响认知健康，无论是总体上还是在易感人群中。因此，我们建议 估计环境中暴露于美国环保局监管的标准空气污染物(目标1)和 颗粒物空气污染成分(目标2)与阿尔茨海默病和相关痴呆症的关系 和相关结果，总体上和潜在易感人群(目标3)。虽然我们将考虑多个 空气污染物，我们的拨款重点是测试假设，较高的中年和累积，中年到晚年 暴露于细颗粒物(PM2.5)、臭氧(O3)和特定金属(Cd、V、Mn、Ni、V、铬和铅)是 与偶发痴呆症及相关后果有关。为了实现这些目标，我们将使用来自 社区动脉粥样硬化风险(ARIC)研究，收集了令人难以置信的纵向数据的独特队列 从中年到晚年。我们将估计每个参与者住址的空气污染物暴露量 在25年的随访中，从中年到晚年，使用集合/数据融合方法结合 两种化学品运输模型(CMAQ、UCD/CTI)、两种排放清单(NEI和EDGAR)，可供使用 监测数据和局部分散模型，以最大限度地提高预测精度。然后我们将评估是否 中年暴露或从中年到晚年的累积暴露影响(I)从中年到中年认知能力下降 晚年(n=14,040)，(Ii)在随访期间根据研究标准系统评估偶发痴呆症 UP(n=14,040)或(Iii)有代表性的晚年痴呆相关病理的神经影像证据 ARIC参与者子集(n=1,841)。我们还将进行广泛的敏感性分析，以解决剩余问题 由于使用估计曝光造成的混杂、选择偏差和测量误差/不确定度。 在整个过程中，我们将利用外部咨询小组来确保尽可能好的科学和铺设 为未来的合作奠定基础。为了建议或制定有效的干预措施以减少 痴呆症负担通过减少环境空气污染暴露，我们必须首先确定是否有 特定污染物与阿尔茨海默病和相关痴呆症之间的联系，以及哪些群体 受影响最大的。拟议的工作将提供回答这些问题所需的证据。

PROJECT SUMMARY/ABSTRACT The burden of Alzheimer’s disease and related dementia is substantial and growing. We have no disease- modifying treatments for most dementia sub-types, including Alzheimer’s disease dementia, and recent Alzheimer’s disease treatment trials have been disappointing. Thus, identifying ways to prevent or delay Alzheimer’s disease and related dementia may be our best option for reducing disease burden. Ambient air pollution exposure is a promising target for interventions to prevent or delay Alzheimer’s disease and related dementia. While the existing evidence linking ambient air pollution exposures to cognitive health and dementia is suggestive, it is insufficient to justify action. In order to recommend or develop effective interventions to reduce dementia burden through reductions in ambient air pollution exposure, we must first establish whether specific pollutants impact cognitive health, either overall or in susceptible subgroups. Thus, we propose to estimate associations between ambient exposure to U.S. EPA-regulated criteria air pollutants (Aim 1) and components of particulate matter air pollution (Aim 2) with incident Alzheimer’s disease and related dementia and related outcomes, overall and in potentially susceptible subgroups (Aim 3). While we will consider multiple air pollutants, our grant focuses on testing hypotheses that higher midlife and cumulative, mid- to late-life exposures to fine particulate matter (PM2.5), ozone (O3), and specific metals (Cd, V, Mn, Ni, V, Cr, and Pb) are associated with incident dementia and related outcomes. To complete these aims, we will use data from the Atherosclerosis Risk in Communities (ARIC) study, a unique cohort with incredible longitudinal data collected from midlife to late life. We will estimate exposure to air pollutants at each participant’s residential address throughout 25 years of follow-up, from midlife to late life, using an ensemble/data-fusing approach combining two chemical transport models (CMAQ, UCD/CTI), two emission inventories (NEI and EDGAR), available monitor data, and a local dispersion model, to maximize prediction accuracy. We will then evaluate whether midlife exposures or cumulative exposures from midlife to late life impact (i) cognitive decline from midlife to late life (n=14,040), (ii) incident dementia systematically assessed according to research criteria during follow- up (n=14,040), or (iii) neuroimaging evidence of dementia-related pathology in late life in a representative subset of ARIC participants (n=1,841). We will also conduct extensive sensitivity analyses to address residual confounding, selection bias, and measurement error/uncertainty due to use of estimated exposures. Throughout we will leverage an External Advisory Panel to ensure the best possible science and lay the groundwork for future collaboration. In order to recommend or develop effective interventions to reduce dementia burden through reductions in ambient air pollution exposure, we must first determine whether there is a link between specific pollutants and Alzheimer’s disease and related dementia, as well as what groups are most affected. The proposed work will provide evidence needed to answer to these questions.